SummaryMost hereditary diseases in humans are genetically complex, resulting from combinations of mutations in multiple genes. However synthetic interactions between genes are very difficult to identify in population studies because of a lack of statistical power and we fundamentally do not understand how mutations interact to produce phenotypes. C. elegans is a unique animal in which genetic interactions can be rapidly identified in vivo using RNA interference, and we recently used this system to construct the first genetic interaction network for any animal, focused on signal transduction genes. The first objective of this proposal is to extend this work and map a comprehensive genetic interaction network for this model metazoan. This project will provide the first insights into the global properties of animal genetic interaction networks, and a comprehensive view of the functional relationships between genes in an animal. The second objective of the proposal is to use C. elegans to develop and validate experimentally integrated gene networks that connect genes to phenotypes and predict genetic interactions on a genome-wide scale. The methods that we develop and validate in C. elegans will then be applied to predict phenotypes and interactions for human genes. The final objective is to dissect the molecular mechanisms underlying genetic interactions, and to understand how these interactions evolve. The combined aim of these three objectives is to generate a framework for understanding and predicting how mutations interact to produce phenotypes, including in human disease.

Most hereditary diseases in humans are genetically complex, resulting from combinations of mutations in multiple genes. However synthetic interactions between genes are very difficult to identify in population studies because of a lack of statistical power and we fundamentally do not understand how mutations interact to produce phenotypes. C. elegans is a unique animal in which genetic interactions can be rapidly identified in vivo using RNA interference, and we recently used this system to construct the first genetic interaction network for any animal, focused on signal transduction genes. The first objective of this proposal is to extend this work and map a comprehensive genetic interaction network for this model metazoan. This project will provide the first insights into the global properties of animal genetic interaction networks, and a comprehensive view of the functional relationships between genes in an animal. The second objective of the proposal is to use C. elegans to develop and validate experimentally integrated gene networks that connect genes to phenotypes and predict genetic interactions on a genome-wide scale. The methods that we develop and validate in C. elegans will then be applied to predict phenotypes and interactions for human genes. The final objective is to dissect the molecular mechanisms underlying genetic interactions, and to understand how these interactions evolve. The combined aim of these three objectives is to generate a framework for understanding and predicting how mutations interact to produce phenotypes, including in human disease.

SummaryMost of the lymphomas diagnosed in the western world are originated from mature B cells. The hallmark of these malignancies is the presence of recurrent chromosome translocations that usually involve the immunoglobulin loci and a proto-oncogene. As a result of the translocation event the proto-oncogene becomes deregulated under the influence of immunoglobulin cis sequences thus playing an important role in the etiology of the disease. Upon antigen encounter mature B cells engage in the germinal center reaction, a complex differentiation program of critical importance to the development of the secondary immune response. The germinal center reaction entails the somatic remodelling of immunoglobulin genes by the somatic hypermutation and class switch recombination reactions, both of which are triggered by Activation Induced Deaminase (AID). We have previously shown that AID also initiates lymphoma-associated c-myc/IgH chromosome translocations. In addition, the germinal center reaction involves a fine-tuned balance between intense B cell proliferation and program cell death. This environment seems to render B cells particularly vulnerable to malignant transformation. We aim at studying the molecular events responsible for B cell susceptibility to lymphomagenesis from two perspectives. First, we will address the role of AID in the generation of lymphomagenic lesions in the context of AID specificity and transcriptional activation. Second, we will approach the regulatory function of microRNAs of AID-dependent, germinal center events. The proposal aims at the molecular understanding of a process that lies in the interface of immune regulation and oncogenic transformation and therefore the results will have profound implications both to basic and clinical understanding of lymphomagenesis.

Most of the lymphomas diagnosed in the western world are originated from mature B cells. The hallmark of these malignancies is the presence of recurrent chromosome translocations that usually involve the immunoglobulin loci and a proto-oncogene. As a result of the translocation event the proto-oncogene becomes deregulated under the influence of immunoglobulin cis sequences thus playing an important role in the etiology of the disease. Upon antigen encounter mature B cells engage in the germinal center reaction, a complex differentiation program of critical importance to the development of the secondary immune response. The germinal center reaction entails the somatic remodelling of immunoglobulin genes by the somatic hypermutation and class switch recombination reactions, both of which are triggered by Activation Induced Deaminase (AID). We have previously shown that AID also initiates lymphoma-associated c-myc/IgH chromosome translocations. In addition, the germinal center reaction involves a fine-tuned balance between intense B cell proliferation and program cell death. This environment seems to render B cells particularly vulnerable to malignant transformation. We aim at studying the molecular events responsible for B cell susceptibility to lymphomagenesis from two perspectives. First, we will address the role of AID in the generation of lymphomagenic lesions in the context of AID specificity and transcriptional activation. Second, we will approach the regulatory function of microRNAs of AID-dependent, germinal center events. The proposal aims at the molecular understanding of a process that lies in the interface of immune regulation and oncogenic transformation and therefore the results will have profound implications both to basic and clinical understanding of lymphomagenesis.

SummaryThe search of singularities in incompressible flows has become a major challenge in the area of non-linear partial differential equations and is relevant in applied mathematics, physics and engineering. The existence of such singularities would have important consequences for the understanding of turbulence. One way to make progress in this direction, is to study plausible scenarios for the singularities supported by experiments or numerical analysis. With the more sophisticated numerical tools now available, the subject has recently gained considerable momentum. The main goal of this project is to study analytically several incompressible fluid models. In particular solutions that involve the possible formation of singularities or quasi-singular structures.

The search of singularities in incompressible flows has become a major challenge in the area of non-linear partial differential equations and is relevant in applied mathematics, physics and engineering. The existence of such singularities would have important consequences for the understanding of turbulence. One way to make progress in this direction, is to study plausible scenarios for the singularities supported by experiments or numerical analysis. With the more sophisticated numerical tools now available, the subject has recently gained considerable momentum. The main goal of this project is to study analytically several incompressible fluid models. In particular solutions that involve the possible formation of singularities or quasi-singular structures.

SummaryWith the availability of the essentially complete sequence of the human genome, as well as a rapid development of massive sequencing techniques, the research efforts to understand genetics and disease from a cis standpoint will soon reach an endpoint. However, our emerging knowledge of gene regulation networks reveals that epigenetic regulation of the hereditary information plays crucial roles in various biological events through its influence on processes such as transcription, DNA replication and chromosome architecture. Another scenario in which the control of chromatin structure is crucial is the repair of lesions in genomic DNA. There is mounting evidence, particularly from model organisms such as Saccharomyces cerevisiae, that histone modifying enzymes (acetylases, deacetylases, kinases, …) are essential components of the machinery that maintains genome integrity and thereby guards against cancer, degenerative diseases and ageing. However, little is known about the specific “code” of histone tail modifications that coordinate DNA repair, and the impact that an aberrant “histone code” may have on human health. In CHROMOREPAIR we will systematically analyze the chromatin remodelling process that undergoes at DNA lesions and evaluate the impact that chromatin alterations have on the access, signaling and repair of DNA damage. Furthermore, we propose to translate our in vitro knowledge to the development of mouse models that help us evaluate how modulation of chromatin status impinges on genome maintenance and therefore on cancer and aging. As a provocative line of research and based on our preliminary data, we propose that certain chromatin alterations could not only impair but also in some cases promote a more robust response to DNA breaks, which could be a novel and not yet explored way to potentiate the elimination of pre-cancerous cells.

With the availability of the essentially complete sequence of the human genome, as well as a rapid development of massive sequencing techniques, the research efforts to understand genetics and disease from a cis standpoint will soon reach an endpoint. However, our emerging knowledge of gene regulation networks reveals that epigenetic regulation of the hereditary information plays crucial roles in various biological events through its influence on processes such as transcription, DNA replication and chromosome architecture. Another scenario in which the control of chromatin structure is crucial is the repair of lesions in genomic DNA. There is mounting evidence, particularly from model organisms such as Saccharomyces cerevisiae, that histone modifying enzymes (acetylases, deacetylases, kinases, …) are essential components of the machinery that maintains genome integrity and thereby guards against cancer, degenerative diseases and ageing. However, little is known about the specific “code” of histone tail modifications that coordinate DNA repair, and the impact that an aberrant “histone code” may have on human health. In CHROMOREPAIR we will systematically analyze the chromatin remodelling process that undergoes at DNA lesions and evaluate the impact that chromatin alterations have on the access, signaling and repair of DNA damage. Furthermore, we propose to translate our in vitro knowledge to the development of mouse models that help us evaluate how modulation of chromatin status impinges on genome maintenance and therefore on cancer and aging. As a provocative line of research and based on our preliminary data, we propose that certain chromatin alterations could not only impair but also in some cases promote a more robust response to DNA breaks, which could be a novel and not yet explored way to potentiate the elimination of pre-cancerous cells.

Max ERC Funding

948 426 €

Duration

Start date: 2008-12-01, End date: 2013-11-30

Project acronymCRC PROGRAMME

ProjectDissecting the roles of the beta-catenin and Tcf genetic programmes during colorectal cancer progression

SummaryMost colorectal cancers (CRCs) are initiated by activating mutations in components of the Wnt signalling pathway. Physiological Wnt signals are required for the specification and maintenance of the stem and progenitor cell compartments of the intestinal crypts. We demonstrated that early colorectal lesions exhibit a constitutive Wnt target gene programme, which is very similar to that of normal intestinal stem and progenitor cells. We originally proposed that colorectal adenomas behave as clusters of intestinal cells locked into a constitutive crypt progenitor phenotype. Given the prevalence of Wnt signalling mutations in CRC, an outstanding endeavour is the characterization of the similarities and differences in the instructions dictated by beta-catenin and Tcf to normal intestinal cells vs. CRC cells. Here, we propose to systematically compare and catalogue the beta-catenin/Tcf genetic programmes in intestinal progenitor/stem cells, intestinal adenomas and late CRCs. Transcriptomic analysis of isolated normal progenitor cells and tumor cell populations combined with bioinformatic analysis of gene regulatory networks will allow us to workout the hierarchical interactions downstream of beta-catenin and Tcf. Moreover, functional analysis of key beta-catenin/Tcf target genes using genetically modified mice models will help us to pinpoint which Wnt-controlled functions are essential for tumor maintenance and progression in vivo. Moreover, we seek to understand the tumor suppressor role of EphB2 and EphB3 receptors, two beta-catenin/Tcf target genes in normal crypts and benign colorectal adenomas, that block cancer progression by compartmentalizing tumor cells at the onset of CRC. Overall, our results will shed light on the relationship between stem/progenitor cells and cancer and hold potential for the future development of both therapeutic and diagnostic tools.

Most colorectal cancers (CRCs) are initiated by activating mutations in components of the Wnt signalling pathway. Physiological Wnt signals are required for the specification and maintenance of the stem and progenitor cell compartments of the intestinal crypts. We demonstrated that early colorectal lesions exhibit a constitutive Wnt target gene programme, which is very similar to that of normal intestinal stem and progenitor cells. We originally proposed that colorectal adenomas behave as clusters of intestinal cells locked into a constitutive crypt progenitor phenotype. Given the prevalence of Wnt signalling mutations in CRC, an outstanding endeavour is the characterization of the similarities and differences in the instructions dictated by beta-catenin and Tcf to normal intestinal cells vs. CRC cells. Here, we propose to systematically compare and catalogue the beta-catenin/Tcf genetic programmes in intestinal progenitor/stem cells, intestinal adenomas and late CRCs. Transcriptomic analysis of isolated normal progenitor cells and tumor cell populations combined with bioinformatic analysis of gene regulatory networks will allow us to workout the hierarchical interactions downstream of beta-catenin and Tcf. Moreover, functional analysis of key beta-catenin/Tcf target genes using genetically modified mice models will help us to pinpoint which Wnt-controlled functions are essential for tumor maintenance and progression in vivo. Moreover, we seek to understand the tumor suppressor role of EphB2 and EphB3 receptors, two beta-catenin/Tcf target genes in normal crypts and benign colorectal adenomas, that block cancer progression by compartmentalizing tumor cells at the onset of CRC. Overall, our results will shed light on the relationship between stem/progenitor cells and cancer and hold potential for the future development of both therapeutic and diagnostic tools.

Max ERC Funding

1 602 817 €

Duration

Start date: 2008-09-01, End date: 2013-08-31

Project acronymGADD45&P38SIGNALING

ProjectRole of the Gadd45 family and p38 MAPK in tumor suppression and autoimmunity

SummaryGadd45 family proteins play a critical role in genomic stability, cell cycle regulation proliferation and apoptosis. Gadd45a is activated by the tumor suppressor gene p53, which is mutated in &gt;50% of human tumors. The lack of GADD45a in mice leads to spontaneous development of an autoimmune disease similar to systemic lupus erythematosus. The molecular mechanisms that cause autoimmunity are poorly understood. Recent evidence suggests that p38 activation is involved in autoimmune development and tumor suppression. We found that Gadd45a negatively regulates p38 activity in T cells by preventing phosphorylation on Tyr323. Inhibition of Tyr323p38 phosphorylation is a potential therapeutic target in several types of leukemia and autoimmune diseases, including lupus and rheumatoid arthritis. The main goals of this project are a) to study the in vivo function of the Gadd45 family and p38 in tumor suppression and autoimmunity, and b) to analyze their molecular mechanisms to identify targets for disease treatment. We will dissect the signaling pathways involved in development of autoimmunity and cancer using a multidisciplinary approach that combines mouse genetic, human epigenetic, biochemical, molecular biological and immunological techniques. Our project involves the characterization of murine models deficient in each member of the Gadd45 family (Gadd45a, Gadd45b, Gadd45g), as well as double- and triple-knockout mice, development of a knock-in model for p38a, in vivo and in vitro analysis of T cell activation, proliferation, apoptosis and differentiation, epigenetic studies of potential targets, and finally, validation of these results in autoimmune disease and cancer patients. The results of this project will help identify new therapeutic targets for autoimmune diseases and/or cancer.

Gadd45 family proteins play a critical role in genomic stability, cell cycle regulation proliferation and apoptosis. Gadd45a is activated by the tumor suppressor gene p53, which is mutated in &gt;50% of human tumors. The lack of GADD45a in mice leads to spontaneous development of an autoimmune disease similar to systemic lupus erythematosus. The molecular mechanisms that cause autoimmunity are poorly understood. Recent evidence suggests that p38 activation is involved in autoimmune development and tumor suppression. We found that Gadd45a negatively regulates p38 activity in T cells by preventing phosphorylation on Tyr323. Inhibition of Tyr323p38 phosphorylation is a potential therapeutic target in several types of leukemia and autoimmune diseases, including lupus and rheumatoid arthritis. The main goals of this project are a) to study the in vivo function of the Gadd45 family and p38 in tumor suppression and autoimmunity, and b) to analyze their molecular mechanisms to identify targets for disease treatment. We will dissect the signaling pathways involved in development of autoimmunity and cancer using a multidisciplinary approach that combines mouse genetic, human epigenetic, biochemical, molecular biological and immunological techniques. Our project involves the characterization of murine models deficient in each member of the Gadd45 family (Gadd45a, Gadd45b, Gadd45g), as well as double- and triple-knockout mice, development of a knock-in model for p38a, in vivo and in vitro analysis of T cell activation, proliferation, apoptosis and differentiation, epigenetic studies of potential targets, and finally, validation of these results in autoimmune disease and cancer patients. The results of this project will help identify new therapeutic targets for autoimmune diseases and/or cancer.

SummaryGlioma is the most common and aggressive tumour of the brain and its most malignant form, glioblastoma multiforme, is nowadays virtually not curable. Very little is known about glioma genesis and progression at the molecular level and not much progress has been achieved in the treatment of this disease during the last years. The understanding of the molecular mechanisms involved in the biology of glioma is essential for the development of successful and rational therapeutic strategies. Our project aims to: 1- Study the role of the TGF-beta, Shh, Notch, and Wnt signal transduction pathways in glioma. These pathways have been implicated in glioma but still not much is known about their specific mechanisms of action. 2- Study of a cell population within the tumour mass that has stem-cell-like characteristics, the glioma stem cells, and how the four mentioned pathways regulate their biology. 3- Study the role of a transcription factor, FoxG1, that has an important oncogenic role in some gliomas and that it is regulated by the four mentioned pathways interconnecting some of them. Our approach will be based on a tight collaboration with clinical researchers of our hospital and the study of patient-derived tumours. We will analyse human biopsies, generate primary cultures of human tumour cells, isolate the stem-cell-like population of patient-derived gliomas and generate mouse models for glioma based on the orthotopical inoculation of human glioma stem cells in the mouse brain to generate tumours with the same characteristics as the original human tumour. In addition, we will also study genetically modified mouse models and established cell lines. We expect that our results will help understand the biology of glioma and cancer, and we aspire to translate our discoveries to a more clinical ambit identifying molecular markers of diagnosis and prognosis, markers of response to therapies, and unveil new therapeutic targets against this deadly disease.

Glioma is the most common and aggressive tumour of the brain and its most malignant form, glioblastoma multiforme, is nowadays virtually not curable. Very little is known about glioma genesis and progression at the molecular level and not much progress has been achieved in the treatment of this disease during the last years. The understanding of the molecular mechanisms involved in the biology of glioma is essential for the development of successful and rational therapeutic strategies. Our project aims to: 1- Study the role of the TGF-beta, Shh, Notch, and Wnt signal transduction pathways in glioma. These pathways have been implicated in glioma but still not much is known about their specific mechanisms of action. 2- Study of a cell population within the tumour mass that has stem-cell-like characteristics, the glioma stem cells, and how the four mentioned pathways regulate their biology. 3- Study the role of a transcription factor, FoxG1, that has an important oncogenic role in some gliomas and that it is regulated by the four mentioned pathways interconnecting some of them. Our approach will be based on a tight collaboration with clinical researchers of our hospital and the study of patient-derived tumours. We will analyse human biopsies, generate primary cultures of human tumour cells, isolate the stem-cell-like population of patient-derived gliomas and generate mouse models for glioma based on the orthotopical inoculation of human glioma stem cells in the mouse brain to generate tumours with the same characteristics as the original human tumour. In addition, we will also study genetically modified mouse models and established cell lines. We expect that our results will help understand the biology of glioma and cancer, and we aspire to translate our discoveries to a more clinical ambit identifying molecular markers of diagnosis and prognosis, markers of response to therapies, and unveil new therapeutic targets against this deadly disease.

SummaryThe main aim of the proposed research line is to develop high-throughput highly sensitive photonic lab-a-DVD platforms for multiple parallel analysis with an extremely high degree of integration. The already existing high-throughput platforms only use the CD platform as a substrate, without any given functionality, conversely, in this research line, in the DVD platform it is proposed the integration of the following elements: (i) polymeric photonic components (high-sensitivity Mach-Zehnder interferometers, diffraction gratings and hollow prisms). (ii) polymeric microfluidics (hydrophobic valves and mixers). (iii) Chemical modification of the surface with functional groups prone to interact with the specific analyte and (iv) the necessary information in the DVD tracks to allow the usage of the proposed system in modified DVD readers. Additionally, a new set-up will be mounted, in which a second DVD-header will be incorporated, in such a way that simultaneous high-throughput photonic measurements could be easily performed. Clearly, as compared to the existing platforms, the presented research line requires the establishment of a dynamic multidisciplinary group comprising experts of photonics, microfluidics and (bio)chemistry and the results obtained therein will allow the definition of an advanced photonic high-throughput lab-on-a-DVD platform that will definitely have a large number of application fields, ranging from molecular diagnosis to analytical chemistry or proteomics.

The main aim of the proposed research line is to develop high-throughput highly sensitive photonic lab-a-DVD platforms for multiple parallel analysis with an extremely high degree of integration. The already existing high-throughput platforms only use the CD platform as a substrate, without any given functionality, conversely, in this research line, in the DVD platform it is proposed the integration of the following elements: (i) polymeric photonic components (high-sensitivity Mach-Zehnder interferometers, diffraction gratings and hollow prisms). (ii) polymeric microfluidics (hydrophobic valves and mixers). (iii) Chemical modification of the surface with functional groups prone to interact with the specific analyte and (iv) the necessary information in the DVD tracks to allow the usage of the proposed system in modified DVD readers. Additionally, a new set-up will be mounted, in which a second DVD-header will be incorporated, in such a way that simultaneous high-throughput photonic measurements could be easily performed. Clearly, as compared to the existing platforms, the presented research line requires the establishment of a dynamic multidisciplinary group comprising experts of photonics, microfluidics and (bio)chemistry and the results obtained therein will allow the definition of an advanced photonic high-throughput lab-on-a-DVD platform that will definitely have a large number of application fields, ranging from molecular diagnosis to analytical chemistry or proteomics.

Max ERC Funding

1 717 200 €

Duration

Start date: 2008-10-01, End date: 2014-09-30

Project acronymINTELEG

ProjectThe Intellectual and Material Legacies of Late Medieval Sephardic Judaism: An Interdisciplinary Approach

SummaryFrom the 13th to the 15th centuries, the Jews of the Iberian Peninsula (Sepharad) lived side by side with Christians and Muslims. Although persistent tensions existed between these three groups, their members also participated in a common artistic, intellectual and scientific endeavour that produced the requisite conditions for the dawn of the European Renaissance. The worldviews of all three communities revolved around their sacred texts—the Hebrew and Christian Bibles and the Qur’an. This project will take as a focal point Judaism and its sacred text, and will explore its role and impact in late medieval society at large. The project will coordinate the research of a group of young scholars doing groundbreaking work in the field, all sharing a cross-cultural and inter-disciplinary perspective. As a group, we will bring under analysis a wide range of concepts—the production of sacred texts as objects, the history of their cataloguing and preservation, the multiple and conflicting interpretations of their contents, their role as social agents that fostered coexistence or created exclusions, their impact in literature and the arts, their relationship with medieval science, and their relationship to Muslim and Christian Scriptures. The project has a special relevance for today’s multicultural and pluralistic Europe, as it can help to minimize fundamentalist readings of the sacred texts, bring about a greater understanding of the historical roots of modern intercultural conflict and, ultimately, contribute to the development of non essentialist theories of race and culture.

From the 13th to the 15th centuries, the Jews of the Iberian Peninsula (Sepharad) lived side by side with Christians and Muslims. Although persistent tensions existed between these three groups, their members also participated in a common artistic, intellectual and scientific endeavour that produced the requisite conditions for the dawn of the European Renaissance. The worldviews of all three communities revolved around their sacred texts—the Hebrew and Christian Bibles and the Qur’an. This project will take as a focal point Judaism and its sacred text, and will explore its role and impact in late medieval society at large. The project will coordinate the research of a group of young scholars doing groundbreaking work in the field, all sharing a cross-cultural and inter-disciplinary perspective. As a group, we will bring under analysis a wide range of concepts—the production of sacred texts as objects, the history of their cataloguing and preservation, the multiple and conflicting interpretations of their contents, their role as social agents that fostered coexistence or created exclusions, their impact in literature and the arts, their relationship with medieval science, and their relationship to Muslim and Christian Scriptures. The project has a special relevance for today’s multicultural and pluralistic Europe, as it can help to minimize fundamentalist readings of the sacred texts, bring about a greater understanding of the historical roots of modern intercultural conflict and, ultimately, contribute to the development of non essentialist theories of race and culture.

Max ERC Funding

719 336 €

Duration

Start date: 2008-09-01, End date: 2012-08-31

Project acronymLATIN INTO HEBREW

ProjectLatin Philosophy into Hebrew: Intercultural Networks in 13th and 14th Century Europe

Researcher (PI)Alexander Fidora Riera

Host Institution (HI)UNIVERSITAT AUTONOMA DE BARCELONA

Call DetailsStarting Grant (StG), SH4, ERC-2007-StG

SummaryThe intercultural networks between Arabic, Christian and Jewish communities of learning during the Middle Ages have played a decisive role in the evolution of Western thought and have helped to shape the European identity. Until now, scholarly research has focused almost exclusively on the transmission of Arabic philosophy and science into Latin. The influence of Latin texts on Jewish thought has been largely neglected. The goal of this project is to study how Latin-Christian texts written at Toledo were received in the Jewish tradition of the 13th and 14th centuries, and to draw an intellectual topography of the intercultural and interreligious networks that extended across Europe. The work will involve the philosophical analysis of various texts together with their translations and reception, showing how the networks between the different religious communities in the Mediterranean can be understood as an attempt to work on a shared philosophical tradition. This tradition provided a common and continuous medium for dialogue between the faiths, based upon a commitment to philosophical reason. Our approach will be combined with historical and philological research on the conditions and methods of transmission and translation of Latin texts into Hebrew. In addition, the project aims at editing and translating some of the Hebrew texts of reference. The project is only possible in a trans-disciplinary research group, for it requires philosophical, historical and philological skills as well as a high degree of familiarity with the different traditions involved.

The intercultural networks between Arabic, Christian and Jewish communities of learning during the Middle Ages have played a decisive role in the evolution of Western thought and have helped to shape the European identity. Until now, scholarly research has focused almost exclusively on the transmission of Arabic philosophy and science into Latin. The influence of Latin texts on Jewish thought has been largely neglected. The goal of this project is to study how Latin-Christian texts written at Toledo were received in the Jewish tradition of the 13th and 14th centuries, and to draw an intellectual topography of the intercultural and interreligious networks that extended across Europe. The work will involve the philosophical analysis of various texts together with their translations and reception, showing how the networks between the different religious communities in the Mediterranean can be understood as an attempt to work on a shared philosophical tradition. This tradition provided a common and continuous medium for dialogue between the faiths, based upon a commitment to philosophical reason. Our approach will be combined with historical and philological research on the conditions and methods of transmission and translation of Latin texts into Hebrew. In addition, the project aims at editing and translating some of the Hebrew texts of reference. The project is only possible in a trans-disciplinary research group, for it requires philosophical, historical and philological skills as well as a high degree of familiarity with the different traditions involved.